Fungicidal pyridyl cyclopropane carboxamides

ABSTRACT

Novel fungicidal pyridyl cyclopropane carboxamides having the general structural formula ##STR1## in which R is selected from the group halogen C 1  -C 3  alkoxy and C 1  -C 3  haloalkoxy, R 1  is selected from the group of --H and --C.tbd.N; and R 2  is selected from the group of --H, 1--CH 3  and 2--CH 3  ; X is O or S; and fungicidally acceptable organic and inorganic salts thereof. These compounds provide excellent control of fungal growth.

This is a continuation of application Ser. No. 193,621, filed May 13,1988, U.S. Pat. No. 4,808,600 which in turn is a divisional ofapplication Ser. No. 036,542, filed Apr. 15, 1987, U.S. Pat. No.4,766,134 which in turn is a continuation-in-part of application Ser.No. 029,116, filed Mar. 23, 1987, now abandoned, which in turn is acontinuation of Ser. No. 859,152, filed May 2, 1986, now abandoned.

BACKGROUND OF THE INVENTION

Fungal infection of crops such as barley, rice, tomatoes, wheat, beans,roses, grapes and other agriculturally important crops can cause heavylosses in both quantity and quality of agricultural products. It istherefore extremely desirable to have means of preventing, controllingor eliminating fungal growth. Much preventive spraying with commercialfungicides is conducted to attempt to prevent the establishment andgrowth of fungi on agriculturally important crops. It would also bedesirable to have a curative fungicide which, on detection of fungalinfestation, could destroy the fungi and eliminate the deleteriouseffects by use of a postinfestation curative spray.

SUMMARY OF THE INVENTION

Novel fungicidal pyridyl cyclopropane carboxamides having the formula##STR2## wherein R is selected from the group consisting of halogen suchas chlorine, fluorine and bromine, preferably chlorine, C₁ -C₃ alkoxysuch as propoxy, ethoxy and methoxy, preferably methoxy, and C₁ -C₃haloalkoxy; R₁ is selected from the group consisting of hydrogen andcyano; R₂ is selected from the group consisting of methyl and hydrogen;X is either oxygen or sulfur; and fungicidally acceptable organic andinorganic salts thereof which are highly effective fungicides for useboth as preventive and curative fungicides are disclosed herein.

The term "fungicide" is used to mean a compound which controls fungalgrowth. "Controls" includes prevention, destruction and inhibition offungal growth. The term "curative" is meant to refer to a post-infectionapplication of a fungicide which establishes control of fungal infectionand prevents development of deleterious effects of the fungi on the hostcrop.

DETAILED DESCRIPTION

The novel fungicidal compounds of this invention are pyridylcyclopropane carboxyamides having the general formula: ##STR3## whereinR is selected from the group consisting of halogen such as chlorine,fluorine and bromine, preferably chlorine, C₁ -C₃ alkoxy such aspropoxy, ethoxy and methoxy, preferably methoxy, and C₁ -C₃ haloalkoxy;R₁ is selected from the group consisting of hydrogen and cyano; and R₂is selected from the group consisting of methyl and hydrogen; X iseither oxygen or sulfur; and fungicidally acceptable organic andinorganic salts thereof.

By the term "halogen" is meant bromine, fluorine and chloride.

By the term "C₁ -C₃ alkoxy" is meant methoxy, ethoxy, propoxy andisopropoxy.

By the term "C₁ -C₃ haloalkoxy" is meant halogen substituted methoxy,ethoxy, propoxy and isopropoxy.

The compounds of this invention can be generally prepared by reacting aproperly substituted 5-aminopyridine with a properly substitutedcyclopropane carboxylic acid chloride in a polar solvent such asdichloromethane in a suitable reactor. It is desirable to maintain anacid scavenger such as pyridine in the reaction vessel. The reactiongenerally will proceed at room temperature but will operate at atemperature range from -30° to 60° C., depending on the substitutions onthe amino pyridine and the cyclopropane carboxylic acid chloride. Thereaction should go to completion within 1 to 3 hours. The resultingproduct is recovered in a conventional manner by washing with an alkalisolution such as NaOH and water, drying over conventional drying agentssuch as magnesium sulfate, and crystallizing in hexane. The thionocarboxamides of this invention are also active. These compounds areprepared in general by reaction of the corresponding amide withphosphorous pentasulfide in a neutral solvent such as benzene, toluene,chloroform, methylenechloride or pyridine. The product is soluble instrong alkali and may be isolated from the reaction mixture in thatmanner by readjustment of the pH of the extract to neutrality. Salts ofthe various pyridyl cyclopropane carboxamides can be conventionallyprepared by reacting at least a molar amount of a Lewis acid with thecarboxamide. Preferably the reaction is run in a solvent for thecarboxamide with heating if necessary. The prepared salt is recoveredfrom the reaction mixture by conventional techniques.

Pyridyl carboxamides of the invention are basic. The unprotonatednitrogen atom of the pyridyl ring can be protonated by an acid, eitherorganic or inorganic. Representative inorganic acids are hydrochloric,nitric, hydrobromic, sulfuric, sulfamic and phosphoric. Representativeorganic acids are acetic, trifluoroacetic, benzoic, benzenesulfonic,p-toluenesulfonic, naphthalenesulfonic, phenylphosphonic andorganophosphonic. The salts so formed are also fungicidal.

EXAMPLE 1 Preparation of N-(2-Methoxy-5-pyridyl)-cyclopropanecarboxamide

5-Amino-2-methoxy pyridine (12.4 grams, 0.10 mole) and 10 milliliters(ml) of pyridine were mixed together in 200 ml dichloromethane in areaction flask. 9.1 ml (0.10 mole) of cyclopropane carboxylic acidchloride was added to the reaction mixture over a period of 2 minutes.The reaction was exothermic and temperature rose to 34° C. The reactionwas allowed to stand for one hour at room temperature, after which thereaction mixture was washed with 200 ml of 5% sodium hydroxide and 100ml of water. The resulting organic phase was separated and dried overanhydrous magnesium sulfate. Crystals formed, so the mixture wasfiltered and washed with 300 ml of acetone and the filtrate evaporatedin vacuo to give a solid that was triturated with hexane to yield 16.7grams, after drying. The product was identified by IR and NMR as thetitle compound, having a melting point of 130°-131° C. This compoundwill be referred to as Compound 1.

EXAMPLE 2 Preparation of N-(2-Methoxy-5-pyridyl)-cyclopropanecarboxamide dodecanoic acid salt

Three grams (0.016 mole) of the compound of Example 1 was dissolved in100 ml of acetone in a 300 ml, one-neck, round-bottom flask by swirling.3.2 g (0.016 mole) dodecanoic acid was added which went into solution.The resulting solution was evaporated on a rotary evaporator, yielding6.2 g, of a white solid having a melting point of 92°-96° C., which wasidentified by nuclear magnetic resonance spectroscopy as the titlecompound. This compound will be known as Compound 7.

EXAMPLE 3 Preparation ofN-(2-methoxy-5-pyridyl)-cyclopropanethiocarboxamide

A solution of 5.0 g of N-(2-methoxy-5-pyridyl)-cyclopropanecarboxamide(0.026 moles) in methylene chloride (100 ml) was refluxed with stirringwith 6.1 g of phosphorous pentasulfide (0.03 moles). The reactionmixture was cooled to room temperature and diluted with chloroform (100ml) and washed with a saturated sodium bicarbonate solution (200 ml).The organic phase was extracted with 5% sodium hydroxide solution (2×100ml). This extract was acidified with concentrated hydrochloric acid topH 7 and extracted with chloroform (3×100 ml). This chloroform extractwas dried over magnesium sulfate and evaporated in vacuo to yield 0.6 gof the desired product having a melting point of 79°-83° C.

Representative compounds of this invention and their physical propertiesare shown in Table I.

                  TABLE I                                                         ______________________________________                                         ##STR4##                                                                     Cmpd.                              n.sub.D.sup.30 or                          No.    R        R1       R2    X   melting point °C.                   ______________________________________                                        1      OCH.sub.3                                                                              H        H     0   130.0-131.0                                2      Cl       H        H     0   167.0-169.0                                3      OCH.sub.3                                                                              CN       H     0   84.0-92.0                                  4      OCH.sub.3                                                                              H        1-CH.sub.3                                                                          0   70.0-74.0                                  5      OCH.sub.3                                                                              H        2-CH.sub.3                                                                          0   66.0-70.0                                  6      hydrochloric acid salt of Cmpd. 1                                                                 144.0-146.0                                        7      dodecanoic acid salt of Cmpd. 1                                                                   92.0-96.0                                          8      2-naphthalene-sulfonic acid salt                                                                  90.0-96.0                                                 of Cmpd. 1                                                             9      acetic acid salt of Cmpd. 1                                                                       112.0-120.0                                        10     benzoic acid salt of Cmpd. 1                                                                      78.0-85.0                                          11     chloromethyl-phosphonic acid                                                                      110.0-118.0                                               salt of Cmpd. 1                                                        12     hydrochloride acid salt of Cmpd. 2                                                                134.0-136.0                                        13     Br       H        H     0   172.0-175.0                                14     phenyl phosphonic acid salt                                                                       108.0-115.0                                               of Cmpd. 1                                                             15     sulfamic acid salt of Cmpd. 1                                                                     131.0-136.0                                        16     trifluoroacetic acid salt                                                                         89.0-93.0                                                 of Cmpd. 1                                                             17     nitric acid salt of Cmpd. 1                                                                       144.0-145.0                                        18     OCH.sub.3                                                                              H        H     S   79.0-83.0                                  19     F        H        H     O   116.0-117.0                                ______________________________________                                    

EXAMPLE 3 Mole Equivalent Preventative Spray Evaluation ProceduresBarley Powdery Mildew (PM)

Northrup King Sunbar 401 barley seed is planted (12 seeds/2" pot) in asandy-loam soil seven days prior to testing. The test compound isdiluted in a 50/50 acetone/water solution to produce concentrationsdecreasing from 0.004 molar. The test solution is then sprayed onto thebarley plants with atomizing sprayers.

Twenty-four hours later, test plants are placed in an inoculation boxequipped with a circulating fan. Barley plants with heavily sporulatingErysiphe gramins lesions are placed in front of the fan to dislodge anddistribute the spores. After two minutes the fan is shut off and thechamber is left closed five minutes for the spores to settle. Inoculatedplants are then placed on an automatic sub-irrigation greenhouse bench.

Results are recorded seven days following inoculation as percent diseasecontrol based on the percent reduction in lesion area as compared to theuntreated control plants. Compound concentrations which provide 90%disease control (CO 90) are determined from dosage/dilution curves.

Leaf Rust (LR)

Seven seeds of Anza wheat are planted in 2" pots in a sandy-loam soil 12days prior to testing. The compound to be tested is diluted with a 50/50acetone/water solution to produce concentrations decreasing from 0.004molar. Twelve ml of test solution are sprayed onto the wheat plants withan atomizing sprayer.

A suspension of Puccinia recondita urediospores is prepared by vacuumingspores from wheat leaves with ureida pustules and suspending 10⁵spores/ml in deionized water plus 0.5% Tween® 20 (polyoxyethylenesorbitan monolaurate). Plants are inoculated 24 hours after treatment byspraying with the spore suspension to runoff, allowing it to dry on theleaves, respraying to runoff, and then placing the plants into a darkmist chamber. Following 48 hours in the mist, plants are moved to asubirrigation greenhouse bench.

Results are recorded ten days following inoculation as percent diseasecontrol based on the percent reduction in lesion area as compared to theuntreated control plants. Compound concentrations which provide 90%disease control (EC 90) are determined from dosage/dilution curves.

Botrytis Bud Blight (BB)

Two white rose petals are placed in a petri dish lined with wet filterpaper. The compound to be tested is diluted with a 50/50 acetone/watersolution to produce concentrations decreasing from 0.004 molar. On halfml of test solution is atomized onto the petals, and allowed to dry.

Inoculum is prepared by adding a 5 mm plug from a two-week old Botrytiscineria culture grown on Elliot's V-8 agar, to 10 ml sterile distilledwater plus 0.5% grape juice. A 20 ul drop of this inoculum suspension isplaced on each petal. Petri dishes with inoculated petals are stored insealed plastic boxes to maintain saturated humidity.

Results are read four days following inoculation as a percent reductionin necrotic area compared to the acetone/water controls. Compoundconcentrations which provide 90% disease control (EC 90) are determinedfrom dosage/dilution curves.

The molar equivalent of 0.004 used as the initial dilution in theseevaluation procedures is equivalent to 750 parts per million (ppm) ofthe amides. All salts tested were adjusted in a solution to 0.004 molarwhich is equivalent to the 750 ppm of the amide from which the salt wasmade.

The results are presented in Table II as an approximate EC 90 in partsper million. The entry (750) indicates partial control at 750 ppm.

                  TABLE II                                                        ______________________________________                                        Cmpd. No.  PM            LR      BB                                           ______________________________________                                         1         200           200     20                                            2         250           750     25                                            3         (750)         500     25                                            4         >750          >750    750                                           5         (750)         200     200                                           6         200           200     70                                            7         200           200     20                                            8         200           200     20                                            9         200           200     20                                           10         200           200     20                                           11         200           200     20                                           12         --            --      80                                           13         (750)         (750)   (750)                                        14         200           200     20                                           15         --            --      20                                           16         --            --      20                                           17         --            --      20                                           18         (750)         (750)   20                                           19         (750)         250     80                                           ______________________________________                                    

EXAMPLE 4 Post-Infection Fungicide Screening Procedures Apple Scab (AS)

Apple seedlings are inoculated by spraying the foliage with Venturiainaequalis using standard procedures 24 hours. Following inoculation thetest compound is applied in solution as a foliage spray at the rate of160 mg/l. Results are determined after sympton development from thereduction in lesion area as compared to the untreated control plants.

Rice Blast (RB)

Six days before inoculation, seedling rice plants are drenched with asolution containg 50 mg test compound/liter of soil. Inoculation withPiricularia oryzae is performed using standard procedures. Results aredetermined after symptom development from the reduction in lesion areaas compared to the untreated control plants.

Wheat Blume Blotch (GB)

Two days before inoculation, the test compound is applied in solution towheat seedlings as a foliage spray at the rate of 500 mg/l. Inoculationwith Septoria nodorum is performed using standard procedures. Resultsare determined after sympton development from the reduction in lesionarea as compared to the untreated control plants.

Wheat Foot Rot (FR)

Wheat seed infected with Fusarium culmorum is treated with 500 mg/kg oftest compound using standard methods. Results are determined aftersymptom development from the reduction in disease as compared to theuntreated control plants.

Activity is reported on the following basis: O=nil; X=light; XX=moderateand XXX=high.

                  TABLE III                                                       ______________________________________                                                   Disease                                                            Cmpd. No.    AS     RB         GB   FR                                        ______________________________________                                        1            XXX    X          XX   X                                         2            0      X          0    X                                         ______________________________________                                    

EXAMPLE 5 CURATIVE SPRAY EVALUATION PROCEDURES Leaf Rust (LR)

Seven seeds of Anza wheat are planted in 2" pots in a sandy loam soil 12days prior to testing. A suspension of Puccinia recondita urediosporesis prepared by vacuuming spores from wheat leaves with uredia pustulesand suspending 10⁵ spores/ml in deionized water plus 0.5% Tween® 20(polyoxyethylene sorbitan monolaurate). Plants are inoculated byspraying with the spore suspension to runoff, allowing it to dry on theleaves, respraying to runoff, and then placing the plants into a mistchamber. Following 48 hours in the mist, plants are moved to asubirrigation greenhouse bench.

The compound to be tested is diluted in a 50/50 acetone/water solutionto produce concentrations decreasing from 0.075%. Fifty hours followinginoculation, the plants are placed on a rotating turntable and sprayedwith the test solution to near runoff with atomizing nozzles. (Time ofinoculation is defined as when plants are placed into the mist chamber.)

Results are recorded ten days following inoculation as percent diseasecontrol based on the percent reduction in lesion area as compared to theuntreated control plants.

                  TABLE III                                                       ______________________________________                                               Cmpd. No.                                                                             LR                                                             ______________________________________                                               1       100                                                                   2       100                                                                   3       100                                                                   4       100                                                                   5       100                                                                   6       100                                                                   7       100                                                                   8       100                                                                   9       100                                                                   10      100                                                                   11      100                                                            ______________________________________                                    

The compounds of this invention are particularly effective againstBotrytis Bud Blight and are particularly effective as preventativefoliar sprays and curative foliar sprays when compared to standardcommercial compounds used as Botrytis preventative and curative sprays.Fungi on which the compounds of the present invention are particularlyeffective are as follows: Botrytis cinerea; Venturia inaequalis;Septoria nodorum; Erysiphe graminis; Fusarium culmorum; Piriculariaoryzae; and Puccinia graminis.

The compounds of the present invention are useful as fungicides,especially as preventative or curative fungicides, and can be applied ina variety of ways at various concentrations. In general, these compoundsand formulations of these compounds can be applied directly to the cropfoliage, the soil in which the crop is growing, or in the irrigationwater for the crop or soil. In practice, the compounds herein definedare formulated into fungicidal compositions, by admixture, infungicidally effective amounts, with the adjuvants and carriers normallyemployed for facilitating the dispersion of active ingredients foragricultural applications, recognizing the fact that the formulation andmode of application of a toxicant may affect the activity of thematerials in a given application. Thus, these active fungicidalcompounds may be formulated as wettable powders, as emulsifiableconcentrates, as powdery dusts, as solutions or as any of several otherknown types of formulations, depending upon the desired mode ofapplication. Preferred formulations for preventative or curativefungicidal applications are wettable powders and emulsifiableconcentrates. These formulations may contain as little as about 0.1% toas much as about 95% or more by weight of active ingredient. Afungicidally effective amount depends upon the nature of the seeds orplants to be treated and the rate of application varies from about 0.05to approximately 25 pounds per acre, preferably from about 0.1 to about10 pounds per acre.

Wettable powders are in the form of finely divided particles whichdisperse readily in water or other dispersants. The wettable powder isultimately applied to the soil or plant either as a dry dust or as adispersion in water or other liquid. Typical carriers for wettablepowders include fuller's earth, kaolin clays, silicas and other readilywet organic or inorganic diluents. Wettable powders normally areprepared to contain about 5% to about 95% of the active ingredient andusually also contain a small amount of wetting, dispersing, oremulsifying agent to facilitate wetting and dispersion.

Dry flowables or water dispersible granules are agglomerated wettablepowders made by either pan granulation or by fluidized bed. The dryflowable is ultimately applied to the soil or plant as a dispersion inwater or other liquid. These granules are dust-free and free flowingwhen dry and yet upon dilution in water, form homogeneous dispersions.Typical carriers for dry flowables include fuller's earth, kaolin clays,silicas and other readily wet organic or inorganic diluents. The dryflowables normally are prepared to contain from about 5% to about 95% ofthe active ingredient and usually contain a small amount of wetting,dispersing or emulsifying agent to facilitate wetting and dispersion.

Emulsifiable concentrates are homogeneous liquid compositions which aredispersible in water or other dispersant, and may consist entirely ofthe active compound with a liquid or solid emulsifying agent, or mayalso contain a liquid carrier, such as xylene, heavy aromatic naphtha,isophorone and other non-volatile organic solvents. For fungicidalapplication, these concentrates are dispersed in water or other liquidcarrier and normally applied as a spray to the area to be treated. Thepercentage by weight of the essential active ingredient may varyaccording to the manner in which the composition is to be applied, butin general comprises about 0.1% to 95% of active ingredient by weight ofthe fungicidal composition.

Typical wetting, dispersing or emulsifying agents used in agriculturalformulations include, for example, the alkyl and alkylaryl sulfonatesand sulfates and their sodium salts; polyhydroxy alcohols; and othertypes of surface-active agents, many of which are available in commerce.The surface-active agent, when used, normally comprises from 0.1% to 15%by weight of the fungicidal composition.

Dusts, which are free-flowing admixtures of the active ingredient withfinely divided solids such as talc, clays, flours and other organic andinorganic solids which act as dispersants and carriers for the toxicant,are useful formulations for many applications.

Pastes, which are homogeneous suspensions of a finely divided solidtoxicant in a liquid carrier such as water or oil, are employed forspecific purposes. These formulations normally contain about 5% to about95% of active ingredient by weight, and may also contain small amountsof a wetting, dispersing or emulsifying agent to facilitate dispersion.For application, the pastes are normally diluted and applied as a sprayto the area to be affected.

EXAMPLES OF TYPICAL FORMULATIONS

    ______________________________________                                        EXAMPLES OF TYPICAL FORMULATIONS                                              ______________________________________                                        Ingredient            Weight %                                                ______________________________________                                        Oil                                                                           Compound 1            1                                                       Oil solvent-heavy aromatic naphtha                                                                  99                                                      Total                 100                                                     Emulsifiable Concentrate                                                      Compound 2            50                                                      Kerosene              45                                                      Emulsifying agent (mixture of long                                            chain ethoxylated polyethers with                                             long chain sulfonate) 5                                                       Total                 100                                                     Emulsifiable Concentrate                                                      Compound 3            90                                                      Kerosene              5                                                       Emulsifying agent (mixture of long                                            chain ethoxylated polyethers with                                             long chain sulfonate) 5                                                       Total                 100                                                     ______________________________________                                        Ingredient        Wt. %    Wt. %    Wt. %                                     ______________________________________                                        Dusts and/or Powders                                                          Compound 4        0.5      50.0     90.0                                      Attapulgite Clay Powder                                                                         93.5     44.0     4.0                                       Sodium lignin sulfonate                                                                         5.0      5.0      5.0                                       Sodium dioctyl sulfosuccinate                                                                   1.0      1.0      1.0                                       Total             100.0    100.0    100.0                                     ______________________________________                                    

Other useful formulations for fungicidal applications include simplesolutions of the active ingredient in a dispersant in which it iscompletely soluble at the desired concentration, such as acetone,alkylated naphthalenes, xylene and other organic solvents. Pressurizedsprays, typically aerosols, wherein the active ingredient is dispersedin finely divided form as a result of vaporization of a low boilingdispersant solvent carrier, such as the Freons, may also be used.

The fungicidal compositions of this invention are applied to the plantsin the conventional manner. Thus, the dust and liquid compositions canbe applied to the plant by the use of power-dusters, boom and handsprayers and spray dusters. The compositions can also be applied fromairplanes as a dust or a spray because they are effective in lowdosages.

We claim:
 1. A compound having the structural formula ##STR5## in whichR is selected from the group consisting of halogen, C₁ -C₃ alkoxy and C₁-C₃ haloalkoxy, R₁ is --H; and R₂ is selected from the group consistingof --H, 1--CH₃ and 2--CH₃ ; X is O or S: or a fungicidally acceptableorganic or inorganic salt thereof.
 2. The compound of claim 1 wherein Xis O.
 3. The compound of claim 2 wherein R is --Br, R₁ is --H and R₂ is--H.
 4. The compound of claim 2 wherein R is --Cl, R₁ is --H and R₂ is--H.
 5. The compound of claim 2 wherein R is --F, R₁ is --H and R₂ is--H.
 6. A fungicidal composition comprising a fungicidally effectiveamount of a compound having the structural formula ##STR6## in which Ris selected from the group consisting of halogen, C₁ -C₃ alkoxy and C₁-C₃ haloalkoxy, R₁ is --H; and R₂ is selected from the group consistingof --H, 1--CH₃ and 2--CH₃ ; X is O or S: or a fungicidally acceptableorganic or inorganic salt thereof.
 7. The method of controlling fungicomprising applying to the area where control is desired, a fungicidallyeffective amount of a compound having the formula ##STR7## in which R isselected from the group consisting of halogen, C₁ -C₃ alkoxy and C₁ -C₃haloalkoxy, R₁ is --H; and R₂ is selected from the group consisting of--H, 1--CH₃ and 2--CH₃ ; X is O or S: or a fungicidally acceptableorganic or inorganic salt thereof.
 8. The method of claim 7 wherein X isO.
 9. The method of claim 8 wherein R is --Br, R₁ is --H and R₂ is --H.10. The method of claim 8 wherein R is --Cl, R₁ is --H and R₂ is --H.11. The method of claim 8 wherein R is --F, R₁ is --H and R₂ is --H.